Balancing act in liver fibrosis

CXCR7, one of the few chemokine receptors
against which there are virtually no drug development efforts, may be a novel
target for liver fibrosis, according to new findings from a U.S. team.1
The results also pointed to the well-trodden family member CXCR4 in the indication, and the next
steps are to figure out whether to deliver systemic or liver-specific
modulators of the targets.

Liver
fibrosis is the result of aberrant healing processes in response to acute or
chronic liver injury. Although liver endothelial cells are capable of
triggering liver regeneration following acute injury,2-4 chronic
injury can overactivate endothelial cells, thereby promoting fibrosis instead
of regeneration for reasons that are poorly understood.

Because
endothelial cells also are involved in organ development during embryogenesis,
a U.S. team led by Shahin Rafii hypothesized that liver development and
regeneration might share endothelial cell signaling pathways that could be
targeted to prevent or treat liver fibrosis.

The
team found clues supporting this hypothesis in published studies. The papers
showed that signaling between chemokine CXC motif ligand 12
(Cxcl12; Sdf-1) and its receptors-Cxcr7 (CXC chemokine receptor 7)
and Cxcr4 (Npy3r)-on endothelial cells was required
for normal embryonic development of the GI tract and heart in mice and might be
involved in pathological remodeling of those tissues after injury.5-7

To
determine whether the SDF-1 signaling pathway plays a role in liver
regeneration and fibrosis, the team began by examining the effects of acute and
chronic liver injury on levels of Cxcr7 and Cxcr4 in mouse models.

The
team found that acute liver injury increased Cxcr7 levels on liver endothelial
cells compared with no injury but did not affect Cxcr4 levels. Chronic liver
injury increased levels of Cxcr7, Cxcr4 and fibroblast growth factor receptor 1 (Fgfr1; Cd331) on liver endothelial cells
compared with cells from uninjured controls.

Next,
the team looked at mouse models of chronic liver injury that had endothelial
cell-specific knockout of Cxcr7, Cxcr4 or Fgfr1. Cxcr7
deficiency decreased levels of inhibitor of DNA binding 1 (Id1)-a transcription factor essential for
liver regeneration2-and increased hepatic levels of collagen and
other profibrotic factors compared with wild-type expression. Conversely, deficiency
in Cxcr4 or Fgfr1 decreased hepatic levels of collagen and other
profibrotic factors.

Lastly,
the team showed that SDF-1 or a CXCR7 agonist upregulated proregenerative ID1
in wild-type human liver endothelial cell culture. SDF-1 did not upregulate ID1
in liver endothelial cells deficient in either CXCR4 or CXCR7-indicating
that induction of ID1 requires cooperation between the two receptors, the team
wrote in its report in Nature.

Seventh
heaven

Collectively, the findings show that
agonizing CXCR7, or antagonizing CXCR4 or FGFR1, might treat or prevent liver
fibrosis, Rafii told SciBX. Of the three targets, he said that CXCR7
appears most promising.

In
the mouse models "the CXCR7 agonist induced an endothelial cell response
that not only prevented fibrosis but also preferentially stimulated
regeneration," said Rafii. "It's conceivable that specific activation
of CXCR7 would induce regeneration of functional liver tissue and cells while
avoiding irreversible scar formation" after acute liver injury.

Bi-Sen Ding, first author on the study, said that CXCR4
and FGFR1 were less promising because both proteins are involved in normal
wound healing and angiogenesis in many tissues. Moreover, CXCR4 is required to
stimulate proregenerative ID1 in liver endothelial cells.

"Inhibiting CXCR4 or FGFR1 might interfere with
normal healing and regeneration processes that are required for liver repair,"
he said. Ding is an assistant professor of genetic medicine at Weill Cornell.

At
least seven companies have compounds that inhibit FGFR1 in Phase II to Phase
III testing to treat hematological malignancies and solid tumors.

"The
team's results provide a therapeutic road map to achieve hepatic regeneration
without provoking fibrosis following liver injury," said Jim Chen, a
project manager at TCM Biotech International Corp.

TCM's
TCM-808FB is in preclinical development
to treat and prevent liver fibrosis. The company has not disclosed the compound's
target or therapeutic modality.

Chen
said that the team also showed that activation of CXCR7 and CXCR4 on liver
endothelial cells regulated the recruitment of macrophages and inflammatory
molecules involved in liver regeneration and fibrosis. "This suggests that
the balance between those two processes is not determined solely by the two
chemokine receptors," he said.

Thus,
Chen wants to know more about how other immune system and inflammatory factors
affect the CXCR7-ID1 and FGFR1-CXCR4 pathways following liver injury.

He
also said that it is not yet clear whether systemic or liver-specific delivery
of therapies targeting CXCR7 or CXCR4 would be safer and thus preferable.

Rafii
and Ding agreed that further work needs to be done to explore the question of
delivery modes but said that their findings already hint at the answer.

"Systemic
therapies should work to a certain extent," Rafii said. "But
liver-specific delivery-or even liver endothelial cell-specific delivery-would
be the optimal strategy, especially when devising approaches to inhibit CXCR4
or FGFR1," in order to avoid interfering with their roles in healing and
angiogenesis in other organs and tissues.

Alternatively,
priming endothelial cells with SDF-1 or a CXCR7 agonist and then transplanting
the cells into the liver "would be an ideal cell-based therapeutic
strategy to stimulate regeneration without causing fibrosis," Ding said.

Nevertheless,
identifying liver-specific or cell-based therapies for liver fibrosis is not
the team's top priority. "We first plan to test specific agonists of CXCR7
in the mouse models of liver injury to thoroughly investigate the potential
therapeutic value of our findings," Rafii said.

"In
our ongoing work, we also want to delineate the differential functions of CXCR4
in stimulating regeneration and provoking fibrosis," Ding said. "We
hope to identify a specific approach or mechanism that enables proregenerative
cooperation between CXCR4 and CXCR7."

According
to Ding, Weill Cornell has filed a patent application covering the findings,
and the IP is available for licensing.

Access this BioCentury Innovations article article for your individual use via a permanent link that allows you to read or print the article: $100.
The article link will be posted on the purchase transaction web page, and also emailed to you with your purchase confirmation.

Purchase This Article for Limited One-Time Distribution and Posting to Your Website :

Receive a formatted PDF reprint of this article with rights for limited one-time redistribution and posting to your website: $750. Please allow 24-48 hours for delivery.

Purchase Options

Purchase this article for individual use $100 USDPurchase this article for limited one-time distribution and website posting $750 USD